Process for the production of delta9(11) steroids



PROCESS FOR THE PRODUCTION OF A901) STEROIDS Franz Sondheimer, OctavioMancera, and George Rosenkranz, Mexico City, Mexico, assignors to SyntexS.A., Mexico City, Mexico, a corporation of Mexico No Drawing.Application December 17, 1954 Serial No. 476,072

Claims priority, application Mexico December 18, 1953 3 Claims. (Cl.260-3975) The present invention is directed to cy'clopentanophenanthrenecompounds and to a process for the production thereof. p

More particularly the present invention relates to the production of A-steroids by dehydration of the corresponding ll-hydroxycompounds.

Steroidal 11 fl-hydroxy compounds are easily dehydrated to thecorresponding A901) compounds. For example, Shoppee and Reichstein,Helv. Chim. Acta 24, 351 (1941), discloses the dehydration ofll'p-hydr'oxyprogesterone in the presence of hydrochloric-acid to givean active progestational hormone 11 -pregnadiene-3,20- dione(Q-dehydroprogesterone). In general, however, the lla-hydroxy compoundswere consideredto be diificult to dehydrate. 1 V

In accordance with the present-invention, a novel method has beendiscovered for the dehydration of 11ahydroxy steroidal compounds. Therehas, furtherbeen discovered in accordance with the present invention :amethod for the direct dehydration of -11u-hydroxy steroids, particularlywhere these steroids do not contain upunsaturated. keto groupings,involving the reaction of these steroids with phosphorous oxychloride inpyridine. Further, there has been discovered a method for thedehydration of lla-hydroxy steroids involving the formation of thell-tosylate followedbyheating of the tosylate in the presence of atertiary amine such as collidine. In addition, there has been discoveredin accordance 'with the present invention a novel a -steroid which is ause ful intermediate for the-production of theprogestational hormone9-dehydroprogesterone. i I

A portion of the process of the present invention may be illustrated bythe following equations:

Plies horous cry loride Phos horoua oxyc orlde ice ' -In the aboveequation A represents CH .OH or CH-OH and the above equationsillustrates the action of a dehydrating agent on typical llu-hydroxysteroids, i.e., a steroid of the spirostane series and a steroid of thepregnane series. The above equations further illustrate the action ofphosphorous oxychloride and pyridine on certain llB-hydroxy steroids aswell. In the above equa-' tion it will be noted that the 3-hydroxy groupis protected as by the formation of an ester, R representing the residueof any acid ordinarily used for the esterification of steroid alcohols.In general, these acids may be classified as carboxylic acids of lessthan about 10 carbon atoms and especially hydrocarbon carboxylic acids,in-

cad-unsaturated keto group.

The products produced from the lla-hydroxy and from the llfi-hydroxycompounds were identical, namely, the corresponding A901) compounds.These derivatives are valuable intermediates for the production of theknown ventional dehydrobromination.

progestational hormone 9-dehydroprogesterone. Thus A pregnene-3,20-dionemay readily be transformed into 9-dehydroprogesterone by monobrominationto form the corresponding 4-bromo derivative followed by con- In thecase of the sapogenin A 0 compound produced, conventional oxi- Hcompounds 1 q I dative degradation produces the corresponding Aallopregnadiene derivative, which upon selective hydrogenation gives thecorresponding A -allopregnane compound. Oppenauer oxidation of the3-hydroxy group gives the corresponding 3-ketone which may be subjectedto the known method for the introduction of the 4-5 double bond intocompounds of the allo series set forth in U.S. application Serial No.140,152, filed January 23, 1950, now Patent No.,2,715,637.

In the instances'where the lla-hydroxy steroids to beconverted into A9compounds contain an cap-unsaturated keto group as the A -3-keto groupor other groups. eifected by the degradating agents previously referredtov -dehydration is advantageously produced inaccordance with thefollowing equations which as indicated illustrate a process alsoapplicable to the dehydrationof saturated We} qr 4 Tertiary amine '-Ibeat Ts Cl R I R0 l I (3H3 I HCa ('10 C O HO- I I 'IsO- l l I Te 01[Tertiary amine heat In the above equations R has the same meaning asheretofore and Ts represents, as is well known, the tosyl(p-toluene-sulphonyl) radical. Y represents either a double bond orsaturated linkage between (14 and C-S.

In practicing the process above outlined, the ll-hydroxy steroidtogether with p-toluenesulphonyl chloride is dissolved in pyridine andmaintained at room temperature for varying periods of time sufficient toform the p-toluenesulphonate. After at least partial purification thep-toluenesulphonate is then refluxed with a tertiary amine such ascollidine to form the corresponding A901) compound. I

The following examples serve to illustrate but are not intended to limitthe present invention:

Example I A solution of g. of 22a,5a-spirostane-3-[3,1la -diol,

diacetate; the vfractions eluted from the column with hem zene-etherafiorded after crystallization from chloroformaluminamethanol 1.76 g. ofthe desired 3'-monoacetate with M.P. ZOO-202 (3., lab -76 (chloroform).

A solution of 0.2 g. of the 3-monoacetate of22a,5aspirostane-3;8,11a-diol in 2 cc. of anhydrous pyridine was cooledto 0 C. and then mixed with 0.6 cc. of recently distilled phosphorousoxychloride. The mixture was kept for 12 hours at room temperature,cooled in ice and the excess of reagent was decomposed by the cautiousaddition of ice. The product was extracted with ether, and the ethersolution was'washed to neutral and evaporated to dryness.Crystallization from chloroform-methanol yielded 0.1 g. of the acetateof A -22a,Sa-spirosten-3fl- 01 with M.P. 1 9 5-197 C. [ozl 51, identicalto the one'obtained in accordance with Example II.

Example 11 I A solution of 0.5 g of the monoacetate of 22a,5oc-;spirostane-3[3,1la-diol and 0.5 g. of p-toluenesulphonyl chloride in- 5cc. of anhydrous pyridine was maintained for 5 days at room temperature.After the addition of water, the precipitate was filtered and thenchromato graphed in a column of 30 g. of ethyl acetate washed Thefractions eluted from the column with benzene-hexane wereicrystalliz'edfrom acetone-hexane, thus giving 0.41 g. of the p-toluenesulphonate withM.P. l26128 C., [al -49 (chloroform).

0.4 g. of this p-toluenesulphonate was refluxed for 30 minutes with 10cc. of collidine, cooled and poured into water. The product wasextracted with ether, the ether solution was washed to neutral andevaporated to dryness. The residue was chromatographcd in' a'column with30 g. of ethyl acetate washed alumina wd the fractions eluted from thecolumn with chloroform-methanol afiorded 0.21 g. of the acetate of A-22a,5a-spirosten-3,8-ol with M.P. 19749 9? C.,' [al 50 (chloroform).

Example III Example IV 300 mg. of the known pregnan-l1a-ol-3,20-dionedissolved in 2 cc. of anhydrous pyridine was dehydrated with 0.8 cc.of-phosphorous oxychloride at room temperature for 20 hours, inaccordance with the method deof ethyl acetate washed alumina yielded 100mg. of A pregnene-3,20-dione with M.P. 146149 C.

Example V 0.5 g. of p-toluenesulphonyl chloride was added to a solutionof 0.5 g. of pregnan-lla-ol-3,20-dione in 3.5 cc. of anhydrous pyridineand the mixture was kept at room temperature for 3 hrs. Addition ofwater, extraction with ether and crystallization from acetonehexaneafforded 0.37 g. of the p-toluenesulphonate with M.P. l59-160 C., [al+74 (chloroform). I

200 mg. of this p-toluenesulphonate was refluxed for 30 minutes with 2cc. of collidine and the solution was cooled and poured into water. Theproduct was extracted with ether, the ether solution was washed toneutral, dried over sodium sulphate and evaporated to dryness. Theresidue was chromatographed in a column with g. of ethyl acetate washedalumina and the fractions eluted from the column with hexane-benzenewere crystallized from acetone-hexane, thus giving 72 mg. of M-pregnene-3,20-'dione with M.P. 147-149 C., [aJ +58" (chloroform)identical to the one obtained in accordance with Example IV.

Example VI 200 mg. of pregnan-l1B-ol-3,20-dione, prepared in accordancewith U.S. application Serial No. 314,752, filed October 14, 1952, nowabandoned, in 1.5 cc. of anhydrous pyridine was dehydrated with 0.6 cc.of phosphorous oxychloride in accordance with the method described inExample I. There was obtained 80 mg. of A -pregnene- 3,20-dione withM.P. l48-150'C., [al +61 (chloroform), identical to the one obtained inaccordance with Examples IV and V.

Example VII ture and then poured into water. The product was extractedwith chloroform and chromatographed in a column with g. of ethyl acetatewashed alumina. The

fractions eluted from the column with benzene were crystallized fromacetone-hexane, thus yielding 1.1 g. of the p-toluenesulphonate withM.P. 154-155 G, [0:1 +132 (chloroform) 0.5 g. of the p-toluenesulphonatesolution was refluxed for 30 minutes, cooled and diluted with water.Extraction with ether afforded 0.33 g. of a solid product which waschromatographed in a column with 20 g. of ethyl acetate washed alumina.The fractions eluted with hexane-benzene and with benzene werecrystallized from acetone-hexane, thus giving 0.24 g. of A-dehydroprogesterone with M.P. 127l28 C., [111 +17l (chloroform).

We claim:

1. A process for the preparation of M -compounds of the pregnane seriescomprising refluxing the corresponding lla-p-toluenesulphonate withcollidine.

2. A process for the preparation of A -pregnene- 3,20-dione comprisingrefluxing the p-toluenesulphonate of pregnan-l1a-ol-3,20-dione withcollidine.

3. A process for the preparation of A -pregnadiene- 3,20-dionecomprising refluxing the p-toluenesulphonate of A-pregnen-1la-ol-3,20-dione with 'collidine.

References Cited in the file of this patent UNITED STATES PATENTS OTHERREFERENCES Fried, I. Am. Chem. Soc., May 3, 1953, vol. 75, pages2273-74.

I of llu-hydroxy I progesterone was dissolved in 10 cc. of collidine andthe,

2. A PROCESS FOR THE PREPARATTION OF $9(11)-PREGNENE3,20-DIONECOMPRISING REFLUXING THE P-TOLUENESULPHONATE OFPREGNAN-11A-01-3,20-DIONE WITH COLLIDINE.